Combination of Bortezomib and Mitotic Inhibitors Down-Modulate Bcr-Abl and Efficiently Eliminates Tyrosine-Kinase Inhibitor Sensitive and Resistant Bcr-Abl-Positive Leukemic Cells
Publication Date
October 14, 2013
Journal
PLoS ONE
Authors
Octavian Bucur, Andreea Lucia Stancu, Ioana Goganau, Stefana Maria Petrescu, et al
Volume
8
Issue
10
Pages
e77390
DOI
https://dx.plos.org/10.1371/journal.pone.0077390
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0077390
Web of Science
000325887300084
Scopus
84885408946
Mendeley
http://www.mendeley.com/research/combination-bortezomib-mitotic-inhibitors-downmodulate-bcrabl-efficiently-eliminates-tyrosinekinase
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Mendeley | Further Information

{"title"=>"Combination of Bortezomib and Mitotic Inhibitors Down-Modulate Bcr-Abl and Efficiently Eliminates Tyrosine-Kinase Inhibitor Sensitive and Resistant Bcr-Abl-Positive Leukemic Cells", "type"=>"journal", "authors"=>[{"first_name"=>"Octavian", "last_name"=>"Bucur", "scopus_author_id"=>"24464363500"}, {"first_name"=>"Andreea Lucia", "last_name"=>"Stancu", "scopus_author_id"=>"55058715000"}, {"first_name"=>"Ioana", "last_name"=>"Goganau", "scopus_author_id"=>"57198446715"}, {"first_name"=>"Stefana Maria", "last_name"=>"Petrescu", "scopus_author_id"=>"35594777900"}, {"first_name"=>"Bodvael", "last_name"=>"Pennarun", "scopus_author_id"=>"36088022700"}, {"first_name"=>"Thierry", "last_name"=>"Bertomeu", "scopus_author_id"=>"6507358012"}, {"first_name"=>"Rajan", "last_name"=>"Dewar", "scopus_author_id"=>"37461187000"}, {"first_name"=>"Roya", "last_name"=>"Khosravi-Far", "scopus_author_id"=>"7003898121"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "scopus"=>"2-s2.0-84885408946", "sgr"=>"84885408946", "pui"=>"370004916", "isbn"=>"1932-6203", "pmid"=>"24155950", "doi"=>"10.1371/journal.pone.0077390"}, "id"=>"8071d826-1aba-3b3b-88f0-d6242263b09f", "abstract"=>"Emergence of resistance to Tyrosine-Kinase Inhibitors (TKIs), such as imatinib, dasatinib and nilotinib, in Chronic Myelogenous Leukemia (CML) demands new therapeutic strategies. We and others have previously established bortezomib, a selective proteasome inhibitor, as an important potential treatment in CML. Here we show that the combined regimens of bortezomib with mitotic inhibitors, such as the microtubule-stabilizing agent Paclitaxel and the PLK1 inhibitor BI2536, efficiently kill TKIs-resistant and -sensitive Bcr-Abl-positive leukemic cells. Combined treatment activates caspases 8, 9 and 3, which correlate with caspase-induced PARP cleavage. These effects are associated with a marked increase in activation of the stress-related MAP kinases p38MAPK and JNK. Interestingly, combined treatment induces a marked decrease in the total and phosphorylated Bcr-Abl protein levels, and inhibits signaling pathways downstream of Bcr-Abl: downregulation of STAT3 and STAT5 phosphorylation and/or total levels and a decrease in phosphorylation of the Bcr-Abl-associated proteins CrkL and Lyn. Moreover, we found that other mitotic inhibitors (Vincristine and Docetaxel), in combination with bortezomib, also suppress the Bcr-Abl-induced pro-survival signals and result in caspase 3 activation. These results open novel possibilities for the treatment of Bcr-Abl-positive leukemias, especially in the imatinib, dasatinib and nilotinib-resistant CML cases.", "link"=>"http://www.mendeley.com/research/combination-bortezomib-mitotic-inhibitors-downmodulate-bcrabl-efficiently-eliminates-tyrosinekinase", "reader_count"=>12, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>1, "Student > Doctoral Student"=>1, "Researcher"=>3, "Student > Ph. D. Student"=>1, "Student > Master"=>2, "Other"=>1, "Lecturer"=>1, "Professor"=>1, "Unspecified"=>1}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>1, "Student > Doctoral Student"=>1, "Researcher"=>3, "Student > Ph. D. Student"=>1, "Student > Master"=>2, "Other"=>1, "Lecturer"=>1, "Professor"=>1, "Unspecified"=>1}, "reader_count_by_subject_area"=>{"Engineering"=>1, "Biochemistry, Genetics and Molecular Biology"=>2, "Medicine and Dentistry"=>1, "Agricultural and Biological Sciences"=>6, "Chemistry"=>1, "Unspecified"=>1}, "reader_count_by_subdiscipline"=>{"Engineering"=>{"Engineering"=>1}, "Medicine and Dentistry"=>{"Medicine and Dentistry"=>1}, "Chemistry"=>{"Chemistry"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>6}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Unspecified"=>{"Unspecified"=>1}}, "group_count"=>0}

Scopus | Further Information

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1235106"], "description"=>"<p><b>A</b>. K562 leukemic cells were exposed to bortezomib (9nM) with or without paclitaxel (6nM) for 48h. The percentage of cell death was measured with an automated Trypan Blue exclusion method. The combination significantly increased the number of Trypan Blue-positive cells, compared with each drug used alone. The results represent the mean +/- standard deviations (SDs) of 4 measurements/condition for the representative Western blot experiment presented in (B). <b>B</b>. K562 leukemic cells were treated with 9nM bortezomib and 6nM paclitaxel for 48h, followed by detection of the cleaved fragments of caspase 3, and of PARP cleavage. The combined regimen induced significant cleavage of caspases 3, 8 & 9, and PARP, implying caspase activation. <b>C</b>. LAMA84 leukemic cells were exposed to bortezomib (4nM) with or without paclitaxel (5nM), for 48h. The percentage of cell death was measured with an automated Trypan Blue exclusion method. The combination significantly increased the number of Trypan Blue-positive cells, compared with each drug used alone. The results represent the mean +/- standard deviations (SDs) of 5 measurements/condition for the representative Western blot experiment presented in (D). <b>D</b>. LAMA84 leukemic cells were treated with 4nM bortezomib and 5nM paclitaxel for 48h, followed by detection of the cleaved fragments of caspase 3, caspase 8, caspase 9 and of PARP cleavage. The combined regimen significantly enhanced the cleavage of caspases 3, 8, 9 and PARP, suggesting caspase activation. At least 3 separate experiments were performed in each case. β-Actin was used as a loading control; “***” = p<0.0001; “**” = p<0.01;.</p>", "links"=>[], "tags"=>["bortezomib", "paclitaxel", "efficiently", "activates", "caspases", "leukemic", "bcr-abl-positive", "k562", "lama84"], "article_id"=>821683, "categories"=>["Biological Sciences"], "users"=>["Octavian Bucur", "Andreea Lucia Stancu", "Ioana Goganau", "Stefana Maria Petrescu", "Bodvael Pennarun", "Thierry Bertomeu", "Rajan Dewar", "Roya Khosravi-Far"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0077390.g001"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Combined_treatment_of_bortezomib_and_paclitaxel_efficiently_activates_caspases_and_induces_cell_death_in_human_leukemic_Bcr_Abl_positive_K562_and_LAMA84_cell_lines_/821683", "title"=>"Combined treatment of bortezomib and paclitaxel efficiently activates caspases and induces cell death in human leukemic Bcr-Abl-positive K562 and LAMA84 cell lines.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-14 03:05:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/1235108"], "description"=>"<p><b>A</b>. K562 leukemic cells were treated with 9nM bortezomib and 6nM paclitaxel for 48h, followed by detection of the total and phosphorylated protein levels of p38MAPK, JNK 1&2 and ERK 1&2. The combined regimen induced a strong increase in phosphorylation of the p38MAPK and JNK 1&2, and a slight increase in P-ERK 1&2. <b>B</b>. LAMA84 leukemic cells were treated with 4nM bortezomib and 5nM paclitaxel for 48h, followed by detection of the total and phosphorylated protein levels of p38MAPK, JNK 1&2 and ERK 1&2. β-Actin was used as a loading control. One representative experiment from three separate experiments is shown.</p>", "links"=>[], "tags"=>["bortezomib", "paclitaxel", "activation", "stress-dependent", "kinases", "jnk", "cytoprotective", "erk", "k562", "lama84"], "article_id"=>821685, "categories"=>["Biological Sciences"], "users"=>["Octavian Bucur", "Andreea Lucia Stancu", "Ioana Goganau", "Stefana Maria Petrescu", "Bodvael Pennarun", "Thierry Bertomeu", "Rajan Dewar", "Roya Khosravi-Far"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0077390.g002"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cotreatment_with_bortezomib_and_paclitaxel_induces_activation_of_stress_dependent_kinases_JNK_and_p38_but_not_of_the_cytoprotective_ERK_kinases_in_K562_and_LAMA84_cell_lines_/821685", "title"=>"Cotreatment with bortezomib and paclitaxel induces activation of stress-dependent kinases JNK and p38, but not of the cytoprotective ERK kinases in K562 and LAMA84 cell lines.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-14 03:05:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/1235109"], "description"=>"<p><b>A</b>. K562 leukemic cells were treated with 9nM bortezomib and 6nM paclitaxel for 48h, followed by detection of the phosphorylated levels of Bcr-Abl, and of the total and phosphorylated protein levels of STAT3, STAT5, CrkL and Lyn. The combined regimen significantly downregulates the phosphorylation of Bcr-Abl, CrkL and Lyn kinases, the total levels and phosphorylation of STAT5 and the phosphorylation of STAT3 transcription factors. <b>B</b>. LAMA84 leukemic cells were treated with 4nM bortezomib and 5nM paclitaxel for 48h, followed by detection of the phosphorylated levels of Bcr-Abl, and of the total and phosphorylated levels of STAT3, STAT5, CrkL and Lyn. The combined regimen significantly downregulates the phosphorylation of Bcr-Abl, CrkL and Lyn kinases, and the total levels and phosphorylation of STAT5. β-Actin was used as a loading control. One representative experiment from three separate experiments is shown.</p>", "links"=>[], "tags"=>["paclitaxel", "downregulates", "phosphorylated", "bcr-abl", "inhibiting", "downstream", "crkl", "lyn", "kinase-dependent", "k562", "lama84"], "article_id"=>821686, "categories"=>["Biological Sciences"], "users"=>["Octavian Bucur", "Andreea Lucia Stancu", "Ioana Goganau", "Stefana Maria Petrescu", "Bodvael Pennarun", "Thierry Bertomeu", "Rajan Dewar", "Roya Khosravi-Far"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0077390.g003"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Bortezomib_and_paclitaxel_combined_treatment_significantly_downregulates_phosphorylated_Bcr_Abl_levels_inhibiting_the_phosphorylation_activity_of_downstream_STAT3_STAT5_CrkL_and_Lyn_kinase_dependent_pathways_in_K562_amp_LAMA84_cell_lines_/821686", "title"=>"Bortezomib and paclitaxel combined treatment significantly downregulates phosphorylated Bcr-Abl levels, inhibiting the phosphorylation/activity of downstream STAT3/STAT5, CrkL and Lyn kinase-dependent pathways, in K562 & LAMA84 cell lines.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-14 03:05:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/1235111"], "description"=>"<p><b>A</b>. K562 (K562-S) and K562-R leukemic cells were treated with 9nM bortezomib and 6nM paclitaxel for 48h, followed by detection of the total levels and phosphorylation of Bcr-Abl. The combined regimen significantly decreases the phosphorylation of Bcr-Abl in both cell lines. <b>B</b>. LAMA84 (LAMA84-S) and LAMA84-R leukemic cells were treated with 4nM bortezomib and 5nM paclitaxel for 48h, followed by detection of the total levels and phosphorylation of Bcr-Abl. The combined regimen downregulates the total levels and phosphorylation of Bcr-Abl in LAMA84-R and phosphorylation of Bcr-Abl in LAMA84-S. <b>C</b>. Baf3 Bcr-Abl and Baf3 Bcr-Abl T315I cell lines were treated with 7nM bortezomib and 7nM paclitaxel for 48h, followed by detection of the total levels and phosphorylation of Bcr-Abl. The combined regimen decreases the phosphorylation of Bcr-Abl in both cell lines. β-Actin was used as a loading control. One representative experiment from several separate experiments is shown.</p>", "links"=>[], "tags"=>["downregulation", "phosphorylation", "bcr-abl", "tkis-resistant", "lama84-r", "baf3", "displaying", "t315i"], "article_id"=>821688, "categories"=>["Biological Sciences"], "users"=>["Octavian Bucur", "Andreea Lucia Stancu", "Ioana Goganau", "Stefana Maria Petrescu", "Bodvael Pennarun", "Thierry Bertomeu", "Rajan Dewar", "Roya Khosravi-Far"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0077390.g004"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Bortezomib_paclitaxel_combination_induces_downregulation_of_the_total_levels_and_phosphorylation_of_Bcr_Abl_in_TKIs_resistant_K562_R_LAMA84_R_and_Baf3_Bcr_Abl_T315I_displaying_increased_Bcr_Abl_expression_activity_and_or_T315I_mutation_/821688", "title"=>"Bortezomib/paclitaxel combination induces downregulation of the total levels and phosphorylation of Bcr-Abl in TKIs-resistant K562-R, LAMA84-R and Baf3 Bcr-Abl T315I, displaying increased Bcr-Abl expression/activity and/or T315I mutation.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-14 03:05:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/1235113"], "description"=>"<p><b>A</b>. K562 leukemic cells were plated in 75cm<sup>2</sup> flasks (2 x 10<sup>6</sup> cells/30 ml/flask) and treated with 9nM bortezomib, 8nM BI 2536 or the combination, for 60h. Phase contrast microscope images of the untreated or treated cells are presented. A Nikon Eclipse TI-S Inverted Microscope was used (10X objective lens). While single treatments did not significantly change the morphology and number of the cells, the combined treatment induced a change in morphology/shape and a decrease in the number of the cells. <b>B</b>. K562 leukemic cells were plated in 75cm<sup>2</sup> flasks (2 x 10<sup>6</sup> cells/30 ml/flask) and treated with 9nM, 10nM bortezomib, 8nM, 10nM BI 2536 or the combination, for 60h. Viability was measured by Trypan Blue dye exclusion method, using a TC10 Automated Cell Counter (Biorad, USA). The results represent the mean +/- standard deviations (SDs) of 6 measurements/condition for the representative Western blot experiment presented in (C) & (D). <b>C</b>. K562 and K562-R cells were treated with 9nM bortezomib and 8nM BI 2536 for 60h, followed by detection of the cleaved caspase 3, caspase 8, caspase 9 and PARP. The combined regimen significantly enhanced this cleavage, suggesting caspase activation in both K562 and K562-R cell lines. <b>D</b>. K562 and K562-R cells were treated with 9nM bortezomib and 8nM BI 2536 for 60h, followed by the detection of Bcr-Abl and phosphorylated STAT5. The combined treatment resulted in a marked decrease of the total levels of Bcr-Abl, which correlates with a decrease in the phosphorylation of the downstream STAT5 protein, in both K562 and K562-R cells. β-Actin was used as an internal loading control. A total of three independent experiments were performed. “***” = p<0.0001.</p>", "links"=>[], "tags"=>["plk1", "inhibitor", "bi", "2536", "downregulation", "phosphorylation", "downstream", "phosphorylated", "stat5", "caspase-dependent", "tkis-resistant", "k562"], "article_id"=>821690, "categories"=>["Biological Sciences"], "users"=>["Octavian Bucur", "Andreea Lucia Stancu", "Ioana Goganau", "Stefana Maria Petrescu", "Bodvael Pennarun", "Thierry Bertomeu", "Rajan Dewar", "Roya Khosravi-Far"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0077390.g005"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Bortezomib_in_combination_with_the_PLK1_inhibitor_BI_2536_induces_a_significant_downregulation_of_the_total_levels_and_phosphorylation_of_Bcr_Abl_a_decrease_of_downstream_phosphorylated_STAT5_and_a_caspase_dependent_cell_death_in_TKIs_resistant_and_8211_/821690", "title"=>"Bortezomib in combination with the PLK1 inhibitor BI 2536 induces a significant downregulation of the total levels and phosphorylation of Bcr-Abl, a decrease of downstream phosphorylated STAT5 and a caspase-dependent cell death in TKIs-resistant and –sensitive K562 cell lines.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-14 03:05:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/1235114"], "description"=>"<p><b>A</b>. K562 leukemic cells were treated with 9nM bortezomib and 4nM docetaxel for 48h, followed by the detection of total Bcr-Abl levels, phosphorylated Bcr-Abl, cleaved caspase 3 and PARP. The combined treatment resulted in a marked decrease of the total levels and phosphorylation of Bcr-Abl. This effect is associated with an increase in cleavage of both caspase 3 and PARP. <b>B</b>. K562 leukemic cells were treated with 9nM bortezomib and 4nM vincristine for 48h, followed by the detection of total Bcr-Abl levels, phosphorylated Bcr-Abl, cleaved caspase 3 and PARP. The combined treatment resulted in a significant decrease in the total levels and phosphorylation of Bcr-Abl compared with individual treatments. This effect is correlated with an increase in cleavage of both caspase 3 and PARP. β-Actin was used as an internal loading control; “***” = p<0.0001; “*” = p<0.05;.</p>", "links"=>[], "tags"=>["mitotic", "inhibitors", "bortezomib", "downregulation", "bcr-abl", "caspase", "activation", "k562"], "article_id"=>821691, "categories"=>["Biological Sciences"], "users"=>["Octavian Bucur", "Andreea Lucia Stancu", "Ioana Goganau", "Stefana Maria Petrescu", "Bodvael Pennarun", "Thierry Bertomeu", "Rajan Dewar", "Roya Khosravi-Far"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0077390.g006"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Bortezomib_in_combination_with_mitotic_inhibitors_as_a_new_strategy_for_CML_combination_of_bortezomib_with_other_mitotic_inhibitors_induces_downregulation_of_the_Bcr_Abl_phosphorylation_total_levels_and_caspase_activation_in_the_K562_cell_line_/821691", "title"=>"Bortezomib in combination with mitotic inhibitors as a new strategy for CML: combination of bortezomib with other mitotic inhibitors induces downregulation of the Bcr-Abl phosphorylation/total levels and caspase activation in the K562 cell line.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-14 03:05:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/1235116"], "description"=>"<p>Our results show that bortezomib in combination with several mitotic inhibitors, known to suppress mitosis through different mechanisms, is able to downregulate total levels and/or phosphorylation of Bcr-Abl at the Tyr 177 site and to inactivate the Bcr-Abl downstream pathways, mediated by Lyn, CrkL or STAT3/STAT5. These effects are associated with caspase-mediated cell death. Tyr177 phosphorylation mediates Bcr-Abl downstream signaling by inducing the formation of a Lyn-Gab2-Bcr-Abl complex, and is required for Bcr-Abl-induced leukemia [<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0077390#B26\" target=\"_blank\">26</a>,<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0077390#B27\" target=\"_blank\">27</a>]. This binding results in Lyn activation by phosphorylation [<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0077390#B28\" target=\"_blank\">28</a>]. Lyn kinase further regulates survival and responsiveness of CML cells to inhibition of Bcr-Abl kinase [<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0077390#B19\" target=\"_blank\">19</a>]. Interestingly, Lyn can also phosphorylate Tyr177 in Bcr-Abl [<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0077390#B26\" target=\"_blank\">26</a>], resulting in a potential feedback mechanism. The Gab2-Bcr-Abl complex is mediated by Grb2 [<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0077390#B3\" target=\"_blank\">3</a>] and results in activation of downstream proliferative/survival pathways, such as Ras-ERK and PI3K-Akt. Gab proteins couple growth factor and cytokine receptors to downstream proteins, resulting in activation of the downstream pathways Ras-ERK, PI3K-Akt and JAK/STAT pathways [<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0077390#B3\" target=\"_blank\">3</a>,<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0077390#B29\" target=\"_blank\">29</a>]. Bcr-Abl phosphorylates and activates STAT3 and STAT5 transcription factors inducing survival and proliferation. Constitutive activation of STAT3/STAT5 is critical for the maintenance of chronic myeloid leukemia [<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0077390#B20\" target=\"_blank\">20</a>,<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0077390#B30\" target=\"_blank\">30</a>]. Bcr-Abl also binds the C-terminal Proline-rich region of the adaptor protein CrkL [<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0077390#B30\" target=\"_blank\">30</a>]. Bcr-Abl phosphorylates CrkL, an event needed for Bcr-Abl-induced leukemia. CrkL can enhance cell migration and Bcr-Abl-mediated leukemogenesis [<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0077390#B6\" target=\"_blank\">6</a>,<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0077390#B18\" target=\"_blank\">18</a>,<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0077390#B31\" target=\"_blank\">31</a>-<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0077390#B34\" target=\"_blank\">34</a>].</p>", "links"=>[], "tags"=>["mitotic", "inhibitors", "treatments-induced"], "article_id"=>821693, "categories"=>["Biological Sciences"], "users"=>["Octavian Bucur", "Andreea Lucia Stancu", "Ioana Goganau", "Stefana Maria Petrescu", "Bodvael Pennarun", "Thierry Bertomeu", "Rajan Dewar", "Roya Khosravi-Far"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0077390.g007"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Bortezomib_in_combination_with_mitotic_inhibitors_as_a_novel_strategy_for_CML_a_model_of_the_combined_treatments_induced_cell_death_/821693", "title"=>"Bortezomib in combination with mitotic inhibitors as a novel strategy for CML: a model of the combined treatments-induced cell death.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-10-14 03:05:38"}
  • {"files"=>["https://ndownloader.figshare.com/files/1235121", "https://ndownloader.figshare.com/files/1235122", "https://ndownloader.figshare.com/files/1235123", "https://ndownloader.figshare.com/files/1235124", "https://ndownloader.figshare.com/files/1235125", "https://ndownloader.figshare.com/files/1235126", "https://ndownloader.figshare.com/files/1235127"], "description"=>"<div><p>Emergence of resistance to Tyrosine-Kinase Inhibitors (TKIs), such as imatinib, dasatinib and nilotinib, in Chronic Myelogenous Leukemia (CML) demands new therapeutic strategies. We and others have previously established bortezomib, a selective proteasome inhibitor, as an important potential treatment in CML. Here we show that the combined regimens of bortezomib with mitotic inhibitors, such as the microtubule-stabilizing agent Paclitaxel and the PLK1 inhibitor BI2536, efficiently kill TKIs-resistant and -sensitive Bcr-Abl-positive leukemic cells. Combined treatment activates caspases 8, 9 and 3, which correlate with caspase-induced PARP cleavage. These effects are associated with a marked increase in activation of the stress-related MAP kinases p38MAPK and JNK. Interestingly, combined treatment induces a marked decrease in the total and phosphorylated Bcr-Abl protein levels, and inhibits signaling pathways downstream of Bcr-Abl: downregulation of STAT3 and STAT5 phosphorylation and/or total levels and a decrease in phosphorylation of the Bcr-Abl-associated proteins CrkL and Lyn. Moreover, we found that other mitotic inhibitors (Vincristine and Docetaxel), in combination with bortezomib, also suppress the Bcr-Abl-induced pro-survival signals and result in caspase 3 activation. These results open novel possibilities for the treatment of Bcr-Abl-positive leukemias, especially in the imatinib, dasatinib and nilotinib-resistant CML cases.</p> </div>", "links"=>[], "tags"=>["bortezomib", "mitotic", "inhibitors", "down-modulate", "bcr-abl", "efficiently", "eliminates", "tyrosine-kinase", "inhibitor", "resistant", "bcr-abl-positive", "leukemic"], "article_id"=>821698, "categories"=>["Biological Sciences"], "users"=>["Octavian Bucur", "Andreea Lucia Stancu", "Ioana Goganau", "Stefana Maria Petrescu", "Bodvael Pennarun", "Thierry Bertomeu", "Rajan Dewar", "Roya Khosravi-Far"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0077390.s001", "https://dx.doi.org/10.1371/journal.pone.0077390.s002", "https://dx.doi.org/10.1371/journal.pone.0077390.s003", "https://dx.doi.org/10.1371/journal.pone.0077390.s004", "https://dx.doi.org/10.1371/journal.pone.0077390.s005", "https://dx.doi.org/10.1371/journal.pone.0077390.s006", "https://dx.doi.org/10.1371/journal.pone.0077390.s007"], "stats"=>{"downloads"=>0, "page_views"=>0, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Combination_of_Bortezomib_and_Mitotic_Inhibitors_Down_Modulate_Bcr_Abl_and_Efficiently_Eliminates_Tyrosine_Kinase_Inhibitor_Sensitive_and_Resistant_Bcr_Abl_Positive_Leukemic_Cells_/821698", "title"=>"Combination of Bortezomib and Mitotic Inhibitors Down-Modulate Bcr-Abl and Efficiently Eliminates Tyrosine-Kinase Inhibitor Sensitive and Resistant Bcr-Abl-Positive Leukemic Cells", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-10-14 03:05:38"}

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Relative Metric

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